Subject: pKa calculations - digest of replies

From: Jan Pedersen <[email-masked]>
Date: Sun, 1 Mar 1998 12:40:57 +0100 (MET)

Greetings all CCLers,

Some tile ago I sent out a request for methods to calculate pKa values for
small molecules. I have received quite a lot of responses and requests for
some sort of digest of the responses. I am in the process of evaluating
all the methods that I can get my hands on using a set of toy molecules.

Here is currently a poor digest of the replies - for further information
on the individual methods - please contact the primary source.

==========================================================================
A small survey about methods for pKa calculations on small organic
compounds.

Jan T Pedersen 		(Feb. 1998)	[email-masked]
==========================================================================
Dr. Mike Gilson (co-author of UHBD)
[email-masked]
------------------------------

Klopman and Fercu, JCC 15:1041, 1994. (This describes a QSAR used
to predict the pKas of 2500 organic acids).

Dixon and Jurs, JCC 14:1460, 1993.  "Estimation of pKa for organic
oxyacids using calculated atomic charges".  (They have another paper
that prescribes how to compute the atomic charges, I think.)

Finally, some series of analogs can be handled reasonable well
with classical e-static models.  You'd need to know the pKa
of one of the group; the e-static model would then be used
to predict the influence of adding or removing polar groups.
This might not work so well, however, if the added groups
are very close in bonding sequence to the group whose pKa
you want... because the model does not capture through-bond
inductive effects.

QM methods reference :  

Richardson et al, JCC 61:207-217, 1997

==========================================================================
Jens Spanget-Larsen
[email-masked]
-------------------

Claims to have good references in : 

J. Spanget-Larsen: "Structure-reactivity correlations for aza-arenes. 
Proton affinities, pKa values, hydrogen-deuterium exchange rates and 
radical induced C-13 shifts", Journal of Physical Organic Chemistry, 
Vol. 8, pp 496-505 (1995).

==========================================================================
Morten Langgård
[email-masked]
----------------

Uses a program called MolSurf written by Pär Sjöberg, can be obtained by
writing to [email-masked]. Uses Spartan or Gaussian
output to calculate a number of different parameters, eg. pKa.

==========================================================================
David E. Clark
[email-masked]

Victoria Barclay
[email-masked]
----------------------------

Several people have identified the ACD Labs program:

Regarding commercial software for pKa calculations, you might be
interested in our ACD/pKa DB or related software... please see:
http://www.acdlabs.com/products/pka/
The algorithm is described on the page:
http://www.acdlabs.com/products/pka/pka_algo.html

==========================================================================
Andreas Goeller
[email-masked]

Andy Holder
[email-masked]

Shawn Butler
[email-masked]
-------------------------------

Andreas Goeller writes:

Is using semiempirical packages ampac and
vamp. It seems that one can eventually getting pka values by scaling the
results of 

SH + H2O ---> B + H3O+

You have to calculate dG = dHf(0K) + ZPE+ (dH-TdS (300K))+ dGsolv

then log K = -dG/2.303RT

See also the article J Phys Chem 101, 1997, 2959

Andy Holder writes:

Our packages AMPAC and CODESSA will do this quite well.  AMPAC is an excellent 
general purpose semiempirical quantum mechanical program with a graphical user 
interface.  CODESSA is a QSAR/QSPR program that uses data from AMPAC to 
compute over 500 descriptors and perform advanced statistical analysis to 
derive correlations for a variety of purposes.  I will send a packet with some 
brochures and papers describing our products along with some reprints 
describing the use of CODESSA with AMPAC.  In the meantime, you can examine 
our website at http://www.semichem.com.

==========================================================================
Ole Hvilsted
[email-masked]
------------

Identified the PALLAS program from CompuDrug. This program can be obtained
together with a test license from ftp.compudrug.hu. Mor information can be
obtained by mailing to [email-masked].

==========================================================================
Gerald Loeffler
[email-masked]
---------------------

Has identified the DelPhi program from MSI and MEAD from Bashford. More
info about these packages can be found on the web at :
http://www.msi.com
http://www.scripps.edu/bashford/index.html

==========================================================================
Brian Teppen
[email-masked]
---------------

Dr. Sam Karickhoff of the US Environmental Protection Agency has
developed such a program, which I believe is called SPARC.

A relevant paper is 
Hilal, S.H., L.A. Carreira, G.L. Baughman, S.W. Karickhoff and C.M.
Melton. 1994. Estimation of Ionization Constants of Azo Dyes and
Related Aromatic Amines: Environmental Implication. Journal of
Physical Organic Chemistry 7(3):122-141.

The program is probably free of charge, and reasonably well tested
and documented.

-----------------------------------------------------------
			Dr. Jan T. Pedersen	
			Head, Computational Chemistry
			Acadia Pharmaceuticals
			Fabriksparken 58
			2600 Glostrup, DENMARK
			email : [email-masked]
			phone : +45 43 29 30 05
			FAX : +45 43 29 30 30
			Lore : http://www.acadia-pharm.com
-----------------------------------------------------------